Treatment of Parasitic Infection
Parasitic infection is treated, or prevented, by the administration of a drug or drugs, such as xenobiotic chemotherapeutic drugs, to a susceptible or infected host organism. Effective treatment of parasitic infection by drug administration is frequently impaired, however, due to resistance of the parasite to the drug. Such resistance can be “inherent” to the parasite in the sense that the susceptibility of the parasite to the drug has not increased due to widespread use of the drug. Commonly, however, drug resistance of infectious parasites is observed due to evolved resistance associated with widespread treatment with the drug and associated selection pressure for resistant phenotypes. Currently, many infectious parasites are completely or highly resistant to available drugs and drug combinations, and parasites still susceptible to available drugs require treatment with greater doses than previously required, such that complete or effectively complete resistance is foreseeable.
For example, chloroquine resistance in certain species of malaria-causing Plasmodium parasites is so widespread that alternative or combination anti-malarial therapies are now required, and many parasitic species, including malaria-causing Plasmodium species, are now multi-drug resistant. As a further example, the incidence of parasite resistance to avermectins a widely used class of nematicides, acaridices and insecticides in veterinary and human medicine and plant protection, is increasing.
Resistance of infectious parasites to anti-parasitic drugs can be avoided or lessened by rendering the parasites more sensitive to one or more drugs. The calcium channel blocker Verapramil for example has been evaluated for its effect on sensitization of parasites to xenobiotics. However, safe, economical, and effective methods for sensitizing parasites in such a manner are lacking.
Drug Efflux Pumps
Drug efflux pumps are a primary mediator of drug resistance in parasites. Generally drug efflux pumps are cell membrane proteins that function as transporters of xenobiotic compounds within a cell to the exterior of the cell. In the malarial protozoan Plasmodium falciparum, for example, at least three transmembrane proteins are known to mediate chloroquine resistance, namely P-glycoprotein (permeability glycoprotein 1, “P-gp”), also referred to as multidrug resistance (“MDR”) protein, P-glycoprotein homolog 1 (Pgh1,) and Plasmodium falciparummultidrug resistance protein (PfMDR). P-gp is an ATP-dependent drug efflux pump associated with drug and multidrug resistance in cells and organisms, and is known to mediate drug resistance in numerous parasites. B. Ullman, Multidrug Resistance and P-glycoproteins in Parasitic Protozoa, J. Bioenergetics and Biomembranes 27:1:77-84 (1995).
Rifamycin Antibiotics for Parasite Inhibition and or Sensitization
Rifabutin is a member of the rifamycin class of antibiotics, and was approved for use as an antibiotic in the United States in 1992. Although rifabutin has been tested for other antibiotic and anti-inflammatory uses, its most common use remains the treatment of tuberculosis and other Mycobacterium infections. Rifampicin, another member of the rifamycin class of antibiotics, was introduced in 1967 and is also used to treat tuberculosis and similar infections.
Several antibiotics, including tetracycline and rifampicin, have been reported to exhibit antimalarial activity. For example, rifampicin has been reported to prolong survival in mouse models of malaria, while the FCR3TC strain of P. falciparum has been reported to exhibit sensitivity to rifampicin at approximately 3.2 uM (a concentration that has been reported to be both achieved and effective in vivo during tuberculosis therapy) in vitro. Rifampicin was also reported to be effective against the chloroquine-resistant C10 strain of P. falciparum at 2.5 uM in vitro and against murine P. chabaudi infections with pretreatment or daily post-infection treatment post-infection at a dose of 100-200 mg/kg. However, a study of 60 human P. vivax patients found that rifampicin alone was not effective against the parasite. See Alger, N. E. et al., Inhibition of rodent malaria in mice by rifampicin. Nature, 1970. 227(5256): p. 381-2; Geary, T. G. and J. B. Jensen, Effects of antibiotics on Plasmodium falciparum in vitro. Am J Trop Med Hyg, 1983. 32(2): p. 221-5; Strath, M. et al., Antimalarial activity of rifampicin in vitro and in rodent models. Trans R Soc Trop Med Hyg, 1993. 87(2): p. 211-6; Pukrittayakamee, S., et al., Antimalarial effects of rifampin in Plasmodium vivax malaria. Antimicrob Agents Chemother, 1994. 38(3): p. 511-4.